Despite metastasis is responsible for more than 90% death of cancer patients, the genetic alterations that endow tumor cells with metastatic behaviors remain largely unknown. The project seeks to decipher the mechanism underlying metastasis by systematically identifying genes controlling tumor metastasis and progression. We hypothesize that metastatic mutations promote tumor cell invasion by disrupting epithelial cell polarity and reorganizing cytoskeleton. The Specific Aim 1 will systematically identify genes whose mutations cause non-invasive tumors to demonstrate metastatic behaviors, as well as those affect tumor progression. Aim 2 will characterize these genes, determine their functions, and investigate the mechanisms controlling tumor progression and metastasis. Based on a novel tumor model in Drosophila, a mosaic screen closely modeling the clonal nature of human cancer is conducted to identify genes whose mutations promote tumor metastasis and progression. Mutants will be genetically mapped. The responsible genes and the molecular lesions will be determined by DNA sequencing analysis. Experiments will be performed to test whether they affect tissue growth, proliferation, and apoptosis. Mechanistic study will focus on how these genes control epithelial cell polarity, cytoskeleton organization, and how their mutations cause metastatic invasion. The results from these experiments will provide exciting insights into the mechanisms by which these genes control tumor progression and metastasis. This highly innovative project addresses one of the least understood areas of cancer biology, metastasis. This work will provide new information on the mechanism of metastasis and has the potential to uncover new genes and pathways that may be targeted for blocking metastasis and tumor growth.